Metamorphosis of subarachnoid hemorrhage research: from delayed vasospasm to early brain injury

Abstract

Delayed vasospasm that develops 3-7 days after aneurysmal subarachnoid hemorrhage (SAH) has traditionally been considered the most important determinant of delayed ischemic injury and poor outcome. Consequently, most therapies against delayed ischemic injury are directed towards reducing the incidence of vasospasm. The clinical trials based on this strategy, however, have so far claimed limited success; the incidence of vasospasm is reduced without reduction in delayed ischemic injury or improvement in the long-term outcome. This fact has shifted research interest to the early brain injury (first 72 h) evoked by SAH. In recent years, several pathological mechanisms that activate within minutes after the initial bleed and lead to early brain injury are identified. In addition, it is found that many of these mechanisms evolve with time and participate in the pathogenesis of delayed ischemic injury and poor outcome. Therefore, a therapy or therapies focused on these early mechanisms may not only prevent the early brain injury but may also help reduce the intensity of later developing neurological complications. This manuscript reviews the pathological mechanisms of early brain injury after SAH and summarizes the status of current therapies.

Fig. 1

Mechanisms of early brain injury after SAH: A number of changes in cerebral environment and function occur during the first 72 h after SAH. Some of the major changes are listed. See text for explanation. ICP intracranial pressure, CPP cerebral perfusion pressure, CBF cerebral blood flow, NO nitric oxide, NOS nitric oxide synthase, ET-1 endothelin-1

Fig. 2

The timeline of physiological alterations during the first 72 h after SAH. Within seconds after SAH: ICP rises, CBF and CPP fall, and BP increases [17]. Five minutes after SAH: ICP declines towards basal value and CPP and BP recover to the basal value, CBF remains decreased, and CBF autoregulation is impaired [17, 37]. Sixty minutes after SAH: ICP stabilizes to a new plateau that is above the basal value, CPP and BP have recovered, CBF is still decreased, and CBF autoregulation still impaired [17, 37]. Twenty-four hours after SAH: ICP is still at the 60-min value, CPP and BP are recovered, CBF is decreased, and CBF autoregulation is still impaired [140]. Seventy-two hours after SAH: ICP, CPP, and BP are at baseline [140], CBF is recovered or decreased [140], and CBF autoregulation is still impaired [141]. Insert: In animals, the higher the ICP rise at SAH and the lower the 60-min CBF recovery, the smaller the changes of 24 h survival [142]

Fig. 3

The timeline of biochemical alterations during the first 72 h after SAH. Sixty minutes after SAH: Glutamate concentration in cerebral interstitial fluid is increased [23], ventricles swell and brain water content increases [35], and the status of plasma electrolytes at this time is not established. Twenty-four hours after SAH: Glutamate concentration in cerebral interstitial fluid is still increased [143], hydrocephalus [35, 96] and hyponatremia [40, 96] have set in. Seventy-two hours after SAH: Glutamate concentration cerebral interstitial fluid is still increased [143], hydrocephalus [35] and hyponatremia [41] are still present. Insert: SAH patients with large bleeds and poor clinical status at admission are more likely to develop acute hydrocephalus and have poor outcomes [38]

Fig. 4

The timeline of molecular alterations during the first 72h after SAH. Ten minutes after SAH: Cerebral NO level is decreased [59] and platelet aggregates are present in parenchymal vessels [62]. Sixty minutes after SAH: cerebral NO level remains decreased [59], platelet aggregates persist in parenchymal vessels [62], plasma ET-1 level increases [74], oxidative stress is in progress [77, 78], and inflammatory cytokines are expressed [144]. Three hours after SAH: Cerebral NO level is increasing towards recovery [59], platelet aggregates are still present in the cerebral vessels [62], oxidative stress persists [77, 78], and inflammatory cytokines are expressed. Twenty-four hours after SAH: Cerebral NO level increases above basal value [60, 61], platelet aggregation in parenchymal vessels continues [62], plasma ET-1 level remains increased [73], oxidative stress persists [145], expression of inflammatory cytokine persists [144], and their markers appear in serum and CSF [88]. Seventy-four hours after SAH: CSF level of NO [61] and of ET-1 is increased [73], oxidative stress persists [145], CSF inflammatory cytokine level remains increased [88], and blood platelet count remains decreased indicating activation, sequestration/aggregation in the brain [146]. Insert: Antioxidant system activity is decreased and lipid peroxidation products accumulate within 72 h after SAH and correlate well with poor clinical conditions and outcome [79, 145]

Fig. 5

Therapeutic strategies against early brain injury after SAH: A battery of compounds working via different pathways has been examined against early brain injury after experimental SAH. Many of them have also been tested against delayed vasospasm and DIC. See text for explanation. ECE endothelin-converting enzyme, PKC protein kinase C, ERK1/2 extracellular signal-regulated kinase, ET-1 endothelin-1, NO nitric oxide, NOS nitric oxide synthase, GSNO S-nitrosoglutathione, SNP sodium nitroprusside, GTN nitroglycerin, eNOS endothelial nitric oxide synthase